Krios IV-Titan Krios IV at Diamond
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Diamond Proposal Number(s):
[21809]
Open Access
Abstract: Lysine acetylation in histone tails is a key post-translational modification that controls transcription activation. Histone deacetylase complexes remove histone acetylation, thereby repressing transcription and regulating the transcriptional output of each gene. Although these complexes are drug targets and crucial regulators of organismal physiology, their structure and mechanisms of action are largely unclear. Here, we present the structure of a complete human SIN3B histone deacetylase holo-complex with and without a substrate mimic. Remarkably, SIN3B encircles the deacetylase and contacts its allosteric basic patch thereby stimulating catalysis. A SIN3B loop inserts into the catalytic tunnel, rearranges to accommodate the acetyl-lysine moiety, and stabilises the substrate for specific deacetylation, which is guided by a substrate receptor subunit. Our findings provide a model of specificity for a main transcriptional regulator conserved from yeast to human and a resource of protein-protein interactions for future drug designs.
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May 2023
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Y.
Liu
,
D. M.
Sanchez
,
M. R.
Ware
,
E. G.
Champenois
,
J.
Yang
,
J. P. F.
Nunes
,
A.
Attar
,
M.
Centurion
,
J. P.
Cryan
,
R.
Forbes
,
K.
Hegazy
,
M. C.
Hoffmann
,
F.
Ji
,
M.-F.
Lin
,
D.
Luo
,
S. K.
Saha
,
X.
Shen
,
X. J.
Wang
,
T. J.
Martínez
,
T. J. A.
Wolf
Open Access
Abstract: Electrocyclic reactions are characterized by the concerted formation and cleavage of both σ and π bonds through a cyclic structure. This structure is known as a pericyclic transition state for thermal reactions and a pericyclic minimum in the excited state for photochemical reactions. However, the structure of the pericyclic geometry has yet to be observed experimentally. We use a combination of ultrafast electron diffraction and excited state wavepacket simulations to image structural dynamics through the pericyclic minimum of a photochemical electrocyclic ring-opening reaction in the molecule α-terpinene. The structural motion into the pericyclic minimum is dominated by rehybridization of two carbon atoms, which is required for the transformation from two to three conjugated π bonds. The σ bond dissociation largely happens after internal conversion from the pericyclic minimum to the electronic ground state. These findings may be transferrable to electrocyclic reactions in general.
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May 2023
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
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Grace Q.
Gong
,
Benoit
Bilanges
,
Ben
Allsop
,
Glenn
Masson
,
Victoria
Roberton
,
Trevor
Askwith
,
Sally
Oxenford
,
Ralitsa R.
Madsen
,
Sarah E.
Conduit
,
Dom
Bellini
,
Martina
Fitzek
,
Matt
Collier
,
Osman
Najam
,
Zhenhe
He
,
Ben
Wahab
,
Stephen H.
Mclaughlin
,
A. W. Edith
Chan
,
Isabella
Feierberg
,
Andrew
Madin
,
Daniele
Morelli
,
Amandeep
Bhamra
,
Vanesa
Vinciauskaite
,
Karen E.
Anderson
,
Silvia
Surinova
,
Nikos
Pinotsis
,
Elena
Lopez-Guadamillas
,
Matthew
Wilcox
,
Alice
Hooper
,
Chandni
Patel
,
Maria A.
Whitehead
,
Tom D.
Bunney
,
Len R.
Stephens
,
Phillip T.
Hawkins
,
Matilda
Katan
,
Derek M.
Yellon
,
Sean M.
Davidson
,
David M.
Smith
,
James B.
Phillips
,
Richard
Angell
,
Roger L.
Williams
,
Bart
Vanhaesebroeck
Diamond Proposal Number(s):
[28677]
Abstract: Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia–reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development.
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May 2023
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I06-Nanoscience
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O. J.
Amin
,
S. F.
Poole
,
S.
Reimers
,
L. X.
Barton
,
A.
Dal Din
,
F.
Maccherozzi
,
S. S.
Dhesi
,
V.
Novák
,
F.
Krizek
,
J. S.
Chauhan
,
R. P.
Campion
,
A. W.
Rushforth
,
T.
Jungwirth
,
O. A.
Tretiakov
,
K. W.
Edmonds
,
P.
Wadley
Diamond Proposal Number(s):
[26255, 27845]
Open Access
Abstract: Topologically protected magnetic textures are promising candidates for information carriers in future memory devices, as they can be efficiently propelled at very high velocities using current-induced spin torques. These textures—nanoscale whirls in the magnetic order—include skyrmions, half-skyrmions (merons) and their antiparticles. Antiferromagnets have been shown to host versions of these textures that have high potential for terahertz dynamics, deflection-free motion and improved size scaling due to the absence of stray field. Here we show that topological spin textures, merons and antimerons, can be generated at room temperature and reversibly moved using electrical pulses in thin-film CuMnAs, a semimetallic antiferromagnet that is a testbed system for spintronic applications. The merons and antimerons are localized on 180° domain walls, and move in the direction of the current pulses. The electrical generation and manipulation of antiferromagnetic merons is a crucial step towards realizing the full potential of antiferromagnetic thin films as active components in high-density, high-speed magnetic memory devices.
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May 2023
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B16-Test Beamline
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Diamond Proposal Number(s):
[6092]
Abstract: The shape and strain field of a needle domain in a barium titanate single crystal are modelled using a distribution of dislocations and line charges. The arrangement of these dislocations and charges is a result of the balance of modified Peach-Koehler forces acting among the dislocations and a lattice friction assumed to act at each dislocation site. Based on measurements of needle shape by synchrotron X-ray diffraction, dislocation pile-up theory is used to compute the distribution of discrete dislocations along the needle and hence estimate the lattice friction. It is found that the lattice friction in this model is proportional to the opening angle of a wedge-shape needle domain and consistent with the observed magnitude of stress required to mobilize needle domains. The microstrain distribution around an a-a needle domain tip, obtained from X-ray diffraction measurement, is further used to test the dislocation model, with a similar pattern and magnitude of strains identified in the model and the experiment.
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May 2023
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I05-ARPES
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Diamond Proposal Number(s):
[20573, 28919, 32737]
Open Access
Abstract: Diverse emergent correlated electron phenomena have been observed in twisted-graphene layers. Many electronic structure predictions have been reported exploring this new field, but with few momentum-resolved electronic structure measurements to test them. We use angle-resolved photoemission spectroscopy to study the twist-dependent (1° < θ < 8°) band structure of twisted-bilayer, monolayer-on-bilayer, and double-bilayer graphene (tDBG). Direct comparison is made between experiment and theory, using a hybrid k·p model for interlayer coupling. Quantitative agreement is found across twist angles, stacking geometries, and back-gate voltages, validating the models and revealing field-induced gaps in twisted graphenes. However, for tDBG at θ = 1.5 ± 0.2°, close to the magic angle θ = 1.3°, a flat band is found near the Fermi level with measured bandwidth Ew = 31 ± 5 meV. An analysis of the gap between the flat band and the next valence band shows deviations between experiment (Δh = 46 ± 5 meV) and theory (Δh = 5 meV), indicative of lattice relaxation in this regime.
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May 2023
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B21-High Throughput SAXS
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Diamond Proposal Number(s):
[26855]
Open Access
Abstract: Monkeypox virus (MPXV) is a double-stranded DNA virus from the family Poxviridae, which is endemic in West and Central Africa. Various human outbreaks occurred in the 1980s, resulting from a cessation of smallpox vaccination. Recently, MPXV cases have reemerged in non-endemic nations, and the 2022 outbreak has been declared a public health emergency. Treatment optionsare limited, and many countries lack the infrastructure to provide symptomatic treatments. The development of cost-effective antivirals could ease severe health outcomes. G-quadruplexes have been a target of interest in treating viral infections with different chemicals. In the present work, a genomic-scale mapping of different MPXV isolates highlighted two conserved putative quadruplex-forming sequences MPXV-exclusive in 590 isolates. Subsequently, we assessed the G-quadruplex formation using circular dichroism spectroscopy and solution small-angle X-ray scattering. Furthermore, biochemical assays indicated the ability of MPXV quadruplexes to be recognized by two specific G4-binding partners—Thioflavin T and DHX36. Additionally, our work also suggests that a quadruplex binding small-molecule with previously reported antiviral activity, TMPyP4, interacts with MPXV G-quadruplexes with nanomolar affinity in the presence and absence of DHX36. Finally, cell biology experiments suggests that TMPyP4 treatment substantially reduced gene expression of MPXV proteins. In summary, our work provides insights into the G-quadruplexes from the MPXV genome that can be further exploited to develop therapeutics.
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May 2023
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Danny
Broberg
,
Kyle
Bystrom
,
Shivani
Srivastava
,
Diana
Dahliah
,
Benjamin A. D.
Williamson
,
Leigh
Weston
,
David O.
Scanlon
,
Gian-Marco
Rignanese
,
Shyam
Dwaraknath
,
Joel
Varley
,
Kristin A.
Persson
,
Mark
Asta
,
Geoffroy
Hautier
Open Access
Abstract: Calculations of point defect energetics with Density Functional Theory (DFT) can provide valuable insight into several optoelectronic, thermodynamic, and kinetic properties. These calculations commonly use methods ranging from semi-local functionals with a-posteriori corrections to more computationally intensive hybrid functional approaches. For applications of DFT-based high-throughput computation for data-driven materials discovery, point defect properties are of interest, yet are currently excluded from available materials databases. This work presents a benchmark analysis of automated, semi-local point defect calculations with a-posteriori corrections, compared to 245 “gold standard” hybrid calculations previously published. We consider three different a-posteriori correction sets implemented in an automated workflow, and evaluate the qualitative and quantitative differences among four different categories of defect information: thermodynamic transition levels, formation energies, Fermi levels, and dopability limits. We highlight qualitative information that can be extracted from high-throughput calculations based on semi-local DFT methods, while also demonstrating the limits of quantitative accuracy.
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May 2023
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Open Access
Abstract: Fragment merging is a promising approach to progressing fragments directly to on-scale potency: each designed compound incorporates the structural motifs of overlapping fragments in a way that ensures compounds recapitulate multiple high-quality interactions. Searching commercial catalogues provides one useful way to quickly and cheaply identify such merges and circumvents the challenge of synthetic accessibility, provided they can be readily identified. Here, we demonstrate that the Fragment Network, a graph database that provides a novel way to explore the chemical space surrounding fragment hits, is well-suited to this challenge. We use an iteration of the database containing >120 million catalogue compounds to find fragment merges for four crystallographic screening campaigns and contrast the results with a traditional fingerprint-based similarity search. The two approaches identify complementary sets of merges that recapitulate the observed fragment–protein interactions but lie in different regions of chemical space. We further show our methodology is an effective route to achieving on-scale potency by retrospective analyses for two different targets; in analyses of public COVID Moonshot and Mycobacterium tuberculosis EthR inhibitors, potential inhibitors with micromolar IC50 values were identified. This work demonstrates the use of the Fragment Network to increase the yield of fragment merges beyond that of a classical catalogue search.
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May 2023
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I05-ARPES
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Abstract: In recent years, chromium sulphur bromide (CrSBr) has emerged as a promising highly- anisotropic semiconducting two-dimensional (2D) magnetic material to explore spintronics and quantum transport due to its strongly correlated quasiparticle interactions [1]. CrSBr is an A-type layered antiferromagnet; in the bulk material, above the Néel temperature (TN = 132K) it transitions to an intermediate ferromagnetic phase before becoming paramagnetic at high temperature. Experimental work on its fascinating optoelectronic properties has been heavily supported by electronic structure calculations using a variety of methods [2,3], but direct band structure measurements to test these predictions are still lacking. Recent angle- resolved photoemission microscopy (ARPES) measurements of bulk CrSBr were unable to measure below TN due to charging effects [4]. Here, we overcome this limitation through exfoliation of CrSBr flakes onto a template-stripped gold surface (Figure 1a) [5]. Using the nanoARPES endstation of the i05 beamline at Diamond Light Source, ARPES was acquired without charging from thin flakes (~10 nm thick) at temperatures down to < 40 K. Photon energy, and polarisation, dependent measurements confirm a strongly 2D dispersion and link the band dispersions to different atomic orbitals. Temperature-dependent measurements highlight electronic structure changes through the magnetic phase transitions, including shifts of the low energy valence bands and band splitting suggestive of spin-ordering (Figure 1b,c). These results also demonstrate a simple approach for the measurement of the low- temperature band structure of insulating layered materials.
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May 2023
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